PUBLIC ABSTRACT

Prostate cancer is the most common malignancy and the second leading cause of cancer deaths in men in the United States. African-American (AA) men have both a higher incidence and significantly higher mortality rates from prostate cancer than Caucasian (CAU) men. To what extent racial differences observed in prostate cancer incidence and mortality are due to socioeconomic or biological factors remains controversial. A major factor that has inhibited understanding the unique biology of prostate cancer in AA men is the lack of clinical and pathological resources focused specifically on this problem. The vast majority of prostate cancer molecular genetic and biological studies do not take differences in race into account when analyzing the results. This reflects the general under-representation of AA men in such studies, which substantially weakens the statistical power of any subgroup analysis. This is exacerbated by the generally lower percentage of AA patients in most tertiary referral centers where most such studies are performed. While some of the difference in mortality due to prostate cancer can be attributed to socioeconomic factors, a number of studies have shown that there is a still a higher mortality rate from prostate cancer in AA men even after adjustment for socioeconomic factors. Thus, in addition to socioeconomic and cultural factors, biological differences account for some of the disparity in incidence and mortality for prostate cancer in AA men in comparison to CAU men. The central problem addressed in this proposal is to understand the biological basis for the more aggressive clinical behavior of prostate cancer in AA men and to develop predictive tools to help manage prostate cancer in AA men.

We have shown that prostate cancers in AA men have changes in their DNA, specifically losses and gains in specific DNA regions that are different than in Caucasian men. The frequency of loss and gain in specific regions is similar to metastatic prostate cancer in CAU men, which may explain the higher aggressiveness of prostate cancer in AA men. Furthermore, prostate cancers in AA men can be divided into more aggressive and less aggressive subgroups based on the pattern of DNA copy number changes, and these patterns are distinct from those in CAU men. The first major goal of this proposal is to delineate at high resolution these patterns of DNA changes in AA prostate cancers and determine if the changes in DNA structure and expression of genes within the altered DNA regions can be used to predict disease aggressiveness in AA men with prostate cancer. Our studies have a high potential to identify novel biomarkers that may help guide treatment decisions in AA men (i.e., watchful waiting vs. definitive therapy).

We have also identified a previously unreported loss of one copy of the DNA on one end of chromosome 4 that is altered in 30% of prostate cancers in AA men but not in CAU men. We will examine this region in detail to identify the gene in this region whose loss promotes prostate cancer in AA men. This will give further insight into the unique biology of AA prostate cancer. Furthermore, this tumor suppressor gene might be a useful therapeutic target, be used in diagnosis, or be used for prognostic prediction in AA men with prostate cancer.

About Us The CDMRP originated in 1992 via a Congressional appropriation to foster novel approaches to biomedical research in response to the expressed needs of its stakeholders-the American public, the military, and Congress.